Clinical
diagnosis of HIV infection in infants performed poorly and resulted in delayed
diagnosis when compared to virologic testing, a prospective cohort study conducted in Kenya has shown. The findings emphasise the importance of
access to virologic testing for early infant HIV diagnosis in resource-limited
settings.

At
one month of age, 70 children were already infected with HIV (81% of all infections during the study period) but only one was correctly diagnosed by using the World Health Organization’s (WHO) 2008 Integrated Management of Childhood Illness (IMCI) clinical algorithm, Lara C Diener and colleagues report in this secondary analysis of a
four-year prospective cohort study published in the advance online edition of AIDS.

The
study evaluated the performance of the WHO IMCI algorithm for HIV diagnosis in infants, in comparison to virologic and
serologic tests for HIV diagnosis, in 444 HIV-exposed infants born to mothers
with HIV receiving care in Nairobi
between 1999 and 2003.

Using
virologic testing, 86 infants (19%) were diagnosed with HIV infection during the
first year of life.

The
overall sensitivity (true positive), specificity (true negative), positive
predictive value (PPV – the proportion of positive results that are true positives)
and negative predictive value (NPV – the proportion of those with negative results
who are without disease) of IMCI compared to virologic testing (the gold
standard) were 58, 87, 52 and 90%, respectively.

In
other words, only 58% (50/86) were eventually diagnosed by IMCI. While
sensitivity increased with age, using IMCI delayed diagnosis by an estimated
median time of 5.9 months, p<0.0001.

These
findings highlight the limited effectiveness of IMCI as a tool for diagnosis in
early infancy. Supporting the development of rapid virologic point-of-care
diagnostics for this population, where early diagnosis and prompt treatment are critical to survival, the authors stress.

Without
treatment, 50% of HIV-infected infants will die before their second birthday. Current
WHO guidelines recommend starting ART at the time of diagnosis in all children
under two years of age.

IMCI,
a set of standardised clinical algorithms, is used in settings with limited
access to laboratory diagnostics, to diagnose and manage common illnesses in
children. The use of a clinical algorithm to identify paediatric HIV infection
was first validated in 2003. Updated by WHO in 2006 and 2008, identification is
based on the presence of two or more of seven clinical criteria.

In
2010, although the evidence was of low quality. WHO recommended the use of
clinical algorithms and serologic testing where virologic testing was
unavailable, so acknowledging the potential of IMCI as an important screening
tool.

Healthcare workers in resource-poor settings may use IMCI to help make decisions
regarding further HIV testing, starting ART, cotrimoxazole prophylaxis and
infant feeding.

A
wide range of sensitivity (9 to 89%) and specificity (42 to 99%) estimates for HIV clinical algorithms have been reported. Factors affecting this disparity
include age distribution, health status, HIV prevalence, health-worker training
and the diagnostic test chosen.

Given
these findings, together with the pending WHO 2012 review of evidence for the
re-evaluation of clinical algorithms among highly vulnerable infant populations,
longitudinal studies looking at IMCI performance are timely, note the authors.

In
this secondary analysis of a study of HIV-exposed Kenyan infants that looked at
HIV transmission and infant immunity, the authors chose to describe the effect
of age on IMCI performance during the first year of life and the delay in
diagnosis when comparing using IMCI with virologic testing.

Between
July 1999 and November 2002, 410 pregnant HIV-positive women were recruited from
Nairobi City Council maternal-child health clinics.

In total, 444
infants were included in the secondary analysis. Eligibility included those
infants who had survived to at least one month of age and had had, at a minimum, one
virologic test and one clinical assessment in the first year of life.

From
1999 to 2003, monthly clinical assessments and quarterly virologic testing were
performed. In the first year of life, mothers and their infants had a median of
eleven study visits (IQR 8-12). Archived
clinical data were used to compare IMCI sensitivity, specificity, PPV and NPV
with virologic testing.

Among
the 19% (86) children diagnosed during the first year of life using virologic testing,
28 (33%) were diagnosed at their neonatal visit, 42 (49%) by month one, seven
(8%) at month three and the remaining 10% after month three.

In all, 35%
(30/86) of HIV-infected infants died between one and twelve months of age;
median age at death was 5.4 months (IQR=4.3-6.9).

Forty-two per cent (36) of infected infants were never diagnosed using IMCI; 14 (39%) died and 5
(14%) were lost to follow-up before they were a year old. Thirteen of the 14 deaths
were among infants who were diagnosed before the age of one month.

IMCI
sensitivity was found to increase with age, consistent with other studies, reflecting
increased prevalence of opportunistic infections among HIV-infected infants as
they become immunosuppressed. Yet
sensitivity remained low throughout early infancy (one month to ten months),
ranging from 1.4% to 35%.

IMCI
performance was poorest at months one and two, when over 80% of all infections
had already happened. This is a critical time for identifying infected infants
and getting them onto treatment promptly, with the best prospects for reducing
disease and death.

PPV
was also lowest at one month of age (14%) and may present a problem where IMCI
is used as a diagnostic tool to guide the start of ART, rather than a screening
tool. In populations where the maternal HIV status is unknown, PPV could be even
lower, leading to children being misdiagnosed and started on ART
inappropriately.

The
authors believe this to be the first time delay in HIV diagnosis using IMCI has
been described. They note that children who met IMCI criteria in their study
would have been categorised as “HIV exposed/possible HIV”. The recommendation
for appropriate follow-up, the authors note, and sole reliance on these
criteria, can result in considerable delays before a “health worker is prompted
to recommend confirmatory testing and/or referral for early start of ART”.

The
authors note that otitis and parotitis were not associated with HIV infection
in this study and suggest their removal from the algorithm be considered.

Strengths
of the study include a prospective longitudinal cohort with a high power to determine time
trends and an unbiased assessment of IMCI clinical criteria.

Sensitivity
estimates were probably reduced because of the high death rate among
HIV-infected infants who were lost to follow-up or died before presenting with
IMCI-specific symptoms at clinic visits.

The
authors note they used a “snapshot” approach in which they assessed clinical
criteria at a specific visit. They believe this is closer to a real-life
situation where most children present to medical officers without access to previous
clinical records.

HIV
prevalence, healthcare worker experience, length of breastfeeding/HIV exposure
and infant health status need to be considered before generalising these findings.

The
authors conclude that their findings “underscore the critical need for expanded
access to virologic-based rapid diagnostic technologies for infant HIV
infection in resource-poor settings. Despite its low sensitivity in infants,
IMCI may still prove useful in identifying older children with undiagnosed HIV
infection and children who get infected through late breast milk transmission.”

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

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checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.